The goal of this proposal is to understand how acquired (somatic) mutations in hematopoietic stem cells contribute to atherosclerotic cardiovascular disease (ASCVD). We recently analyzed blood exome sequences to describe a new phenomenon?clonal hematopoiesis of indeterminate potential (CHIP)?and connected CHIP to aging, hematologic cancer, and risk for ASCVD. In this proposal, we seek to understand if CHIP relates to future risk for incident ASCVD, why some people develop somatic mutations in hematopoietic stem cells, why these clones expand and cause disease only in some people, whether CHIP is a causal risk factor for ASCVD, and whether inflammatory mediators are associated with CHIP and incident ASCVD events. We will address these questions in two large prospective cohort studies?the Atherosclerosis Risk in Communities Study (n=15,792) and UK Biobank (n=503,317)?in which exome sequences are/will be available in nearly all for the calling of CHIP status, standard ASCVD risk factors have been measured, extensive blood biomarkers have been assayed, common variant genotypes have been determined using genotyping chips, and ASCVD events have been monitored on prospective follow-up. We propose: Aim 1: To perform somatic variant detection in blood exome sequences in ARIC and UK Biobank participants (combined n>500,000 participants) and test the association of CHIP with incident ASCVD events. We will also test the hypothesis that a dose?response relationship exists between the size of the clone and effect on ASCVD. Aim 2: To identify the behavioral and clinical correlates of prevalent CHIP status in both the ARIC and UK Biobank studies. Using regression models, we will test the hypothesis that behavioral and clinical factors promote the development of CHIP. Aim 3: To identify the genetic correlates of prevalent CHIP status in both the ARIC and UK Biobank studies and to utilize the Mendelian randomization approach to test the hypothesis that CHIP causally relates to ASCVD events in humans. We will use extant genotype data to test the hypothesis that common DNA sequence variation in the germline genome predisposes participants to develop CHIP. We will develop a genetic instrument for CHIP exposure and test for association with ASCVD in a large-scale genetic study (the Million Hearts Project and the Million Veteran Program). Aim 4: To identify the determinants of progression of CHIP in the ARIC study through repeat exome sequencing in a subset of 5426 participants at a mean interval of ~20 years. We will determine CHIP status at two time points and test the hypothesis that behavioral, clinical, biochemical, and/or germline genotypes contribute to CHIP progression. Aim 5: To examine the association of CHIP with inflammation and incident ASCVD events. We will examine the association of inflammation with CHIP prevalence in late middle age and in older age using both a candidate chemokine/cytokine panel and an unbiased large-scale aptamer proteomic array. We will then examine if inflammatory markers correlated with CHIP are also associated with incident ASCVD.